Delving into the Latest Updates on PF-489791 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PDE5A

Mechanism

PDE5A inhibitors(Phosphodiesterase 5A inhibitors)

Therapeutic Areas

Nervous System DiseasesCardiovascular DiseasesEndocrinology and Metabolic Disease+ [3]

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2Diabetic NephropathiesEssential Hypertension+ [4]

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC20H28N8O4S

InChIKeyZUHZNKJIJDAJFD-UHFFFAOYSA-N

CAS Registry853003-48-2

The primary objective of the study is to estimate the effects of different strong enzyme (CYP3A4) inhibitors, itraconazole, diltiazem, or verapamil on the single dose pharmacokinetics of PF-00489791 in healthy volunteers. The study will enroll approximately 18 subjects that are randomized to 1 of 3 treatment groups. The study is also intended to determine the safety and tolerability of single-dose PF- 00489791 when it is administered with steady-state itraconazole, diltiazem, or verapamil.

Start Date01 Jul 2014

Sponsor / Collaborator

Pfizer Inc.

NCT01200394 / CompletedPhase 2

A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP, MULTI-CENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ONCE-DAILY ADMINISTRATION OF A PHOSPHODIESTERASE 5 INHIBITOR (PF-00489791) IN ADULTS WITH TYPE 2 DIABETES AND OVERT NEPHROPATHY

PF-00489791 is an inhibitor of phosphodiesterase type 5. Our hypothesis is that PF-00489791 will enhance the relaxation of blood vessels within the kidney and so reduce blood pressure, improving renal function.

Start Date01 Dec 2010

Sponsor / Collaborator

Pfizer Inc.

NCT01090492 / CompletedPhase 2

A Phase 2a Randomized Double-blinded, Placebo And Active Controlled Two Cohort Two Doses Cross-over Multi-center Clinical Study To Assess Efficacy Of A Once Daily Administration Of A Phosphodiesterase 5 Inhibitor (Pf-00489791) For The Treatment Of Vasospasm In Primary And Secondary Raynaud's Phenomenon

The investigators propose that once daily administration of PF-00489791, a phosphodiesterase inhibitor, will reduce vasospasm and improve symptoms and signs associated with Primary and Secondary Raynaud's Phenomenon.

Start Date04 Aug 2010

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with PF-489791

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100 Translational Medicine associated with PF-489791

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100 Patents (Medical) associated with PF-489791

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4

Literatures (Medical) associated with PF-489791

01 Nov 2016·Journal of the American Society of NephrologyQ1 · MEDICINE

Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy

Q1 · MEDICINE

Article

Author: Scheele, Wim ; Diamond, Susan ; Tamimi, Nihad ; Perros-Huguet, Christelle ; Clerin, Valerie ; Gale, Jeremy ; El Nahas, Meguid ; Walley, Rosalind ; Le, Vu ; Rolph, Timothy ; Grover-Páez, Fernando

Diabetic nephropathy (DN) is the leading cause of ESRD worldwide. Reduced bioavailability or uncoupling of nitric oxide in the kidney, leading to decreased intracellular levels of the nitric oxide pathway effector molecule cyclic guanosine monophosphate (cGMP), has been implicated in the progression of DN. Preclinical studies suggest that elevating the cGMP intracellular pool through inhibition of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5) might exert renoprotective effects in DN. To test this hypothesis, the novel, highly specific, and long-acting PDE5 inhibitor, PF-00489791, was assessed in a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group trial of subjects with type 2 diabetes mellitus and overt nephropathy receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker background therapy. In total, 256 subjects with an eGFR between 25 and 60 ml/min per 1.73 m2 and macroalbuminuria defined by a urinary albumin-to-creatinine ratio >300 mg/g, were randomly assigned 3:1, respectively, to receive PF-00489791 (20 mg) or placebo orally, once daily for 12 weeks. Using the predefined primary assessment of efficacy (Bayesian analysis with informative prior), we observed a significant reduction in urinary albumin-to-creatinine ratio of 15.7% (ratio 0.843; 95% credible interval 0.73 to 0.98) in response to the 12-week treatment with PF-00489791 compared with placebo. PF-00489791 was safe and generally well tolerated in this patient population. Most common adverse events were mild in severity and included headache and upper gastrointestinal events. In conclusion, the safety and efficacy profile of PDE5 inhibitor PF-00489791 supports further investigation as a novel therapy to improve renal outcomes in DN.

01 Sep 2015·International Urology and NephrologyQ4 · MEDICINE

Phosphodiesterase type 5 inhibitors and kidney disease

Q4 · MEDICINE

Review

Author: Tarik Esen ; David Goldsmith ; Baris Afsar ; Alberto Ortiz ; Adrian Covic ; Abduzhappar Gaipov ; Mehmet Kanbay

Chronic kidney disease (CKD) represents a worldwide health problem. Traditionally, the nephroprotective treatment for CKD aims to slow progression to end-stage renal disease and includes dietary protein restriction, correction of metabolic acidosis, and renin-angiotensin system blockers. However, current standard therapeutic options may not be enough for preventing CKD progression in a subset of patients making necessary to develop novel therapeutic options to further slow renal function loss. Phosphodiesterase type 5 (PDE5) inhibitors represent a class of drugs traditionally used to treat erectile dysfunction and pulmonary hypertension. However, recent evidence suggests that PDE5 inhibitors may have additional therapeutic effects, such as cardioprotection and cerebrovascular protection. In the current review, we summarize PDE5 inhibitors' utility in disease states and clinical conditions related to kidney disease such as systemic hypertension and acute and chronic kidney injury and discuss the mechanisms explaining possible kidney protective roles of PDE5 inhibitors. A recently completed phase 2 trials demonstrated that the long-acting PDE5 inhibitor PF-00489791 decreased albuminuria in patients with overt diabetic nephropathy when added on top of renin-angiotensin system blockade.

01 Jun 2009·HypertensionQ1 · MEDICINE

Blood Pressure Lowering Effects of a New Long-Acting Inhibitor of Phosphodiesterase 5 in Patients With Mild to Moderate Hypertension

Q1 · MEDICINE

Article

Author: Wolk, Robert ; Smith, William B. ; Gilbert, James ; Xuan, Dawei ; Neutel, Joel M. ; Pressler, Milton L. ; Rubino, John ; Mancuso, James

Inhibition of phosphodiesterase 5 is an attractive candidate mechanism for blood pressure (BP) lowering. In this study, a novel long-acting phosphodiesterase 5 inhibitor, PF-00489791, was evaluated in 133 patients with mild to moderate hypertension, randomized into 1 of 4 groups: placebo, 4 mg, 10 mg, and 20 mg titrated after 14 days of dosing to 40 mg. Study medication was administered once daily for 28 days. Ambulatory BP monitoring was used. There was a statistically significant decrease (compared with placebo) in mean daytime systolic BP on day 28 at the 10 and 20/40 mg doses (by ≈5 and ≈7 mm Hg, respectively). Changes in mean daytime diastolic BP corresponded with those in systolic BP. The magnitude of BP lowering was greater on day 1 than on days 14 and 28, but the response was sustained between days 14 and 28. PF-00489791 also exerted BP lowering effects on mean 24-hour ambulatory BP. There was a dose-related increase in plasma cGMP concentration (statistically significant at the 20/40 mg dose). There was an increased incidence of headaches at the 10 and 20/40 mg doses (22% and 21%, respectively, compared with 12% with placebo) and an increased incidence of dyspepsia/gastroesophageal reflux disease and musculoskeletal adverse events at the 20/40 mg dose. In conclusion, PF-00489791 causes a clinically meaningful and sustained BP lowering in patients with hypertension. It is generally safe and well tolerated at the clinically efficacious doses.

100 Deals associated with PF-489791

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11736

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Familial Primary Pulmonary Hypertension	Phase 2	US	Pfizer Inc.	01 Apr 2009
Familial Primary Pulmonary Hypertension	Phase 2	ES	Pfizer Inc.	01 Apr 2009
Familial Primary Pulmonary Hypertension	Phase 2	CH	Pfizer Inc.	01 Apr 2009
Familial Primary Pulmonary Hypertension	Phase 2	CA	Pfizer Inc.	01 Apr 2009
Familial Primary Pulmonary Hypertension	Phase 2	RU	Pfizer Inc.	01 Apr 2009
Familial Primary Pulmonary Hypertension	Phase 2	DE	Pfizer Inc.	01 Apr 2009
Familial Primary Pulmonary Hypertension	Phase 2	IN	Pfizer Inc.	01 Apr 2009
Familial Primary Pulmonary Hypertension	Phase 2	SE	Pfizer Inc.	01 Apr 2009
Neuralgia, Postherpetic	Phase 2	US	Pfizer Inc.	09 Apr 2008
Essential Hypertension	Phase 2	US	Pfizer Inc.	27 Feb 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00422461 (CTgov)	Phase 2	Essential Hypertension	135	placebo (Placebo)	oqujilvmdi(sclwjsldoo) = bghuvpovox gebxwnnimu (wfgtjkyamu, feofuwhair - hoxdjaffvq) View more	-	11 Oct 2021
				PF-00489791 (PF-00489791 4 mg)	oqujilvmdi(sclwjsldoo) = fwvdokndfn gebxwnnimu (wfgtjkyamu, fpbhbfrwys - ztyamcqlky) View more
NCT00599638 (CTgov)	Phase 2	Neuralgia, Postherpetic	72	Pregabalin+PF-00489791 (Pregabalin + PF-00489791)	dpjqkfvxds(qptjytzjtb) = diheuiinhz niakrqfier (nigdwyidar, ruxedusfky - bxdltbyngs) View more	-	05 Aug 2021
				Pregabalin (Pregabalin)	dpjqkfvxds(qptjytzjtb) = qtgopcxliv niakrqfier (nigdwyidar, pzjhjpxcwa - dizvpflhoq) View more
NCT01200394 (CTgov)	Phase 2	Diabetes Mellitus, Type 2 \| Diabetic Nephropathies	256	Placebo	iauvpyrdvl(lkuoejgkvs) = papeuqniak mmkfzaoemh (mstesvpidg, ogcbqtlcou - wwvnhluxrd) View more	-	12 Mar 2019
NCT01090492 (CTgov)	Phase 2	Raynaud Disease \| Vasospasm	243	PF-00489791 (PF-00489791 4 mg (PRP))	qhgyqdpagl(jklpgtzmci) = fphijwhmen xwtgkxzzlq (picalyxhpa, dqqiwdxnzc - uwpataqeox) View more	-	16 May 2018
				PF-00489791 (PF-00489791 20 mg (PRP))	qhgyqdpagl(jklpgtzmci) = fxoqoswxcp xwtgkxzzlq (picalyxhpa, hqtikhiorq - krskvkrtsv) View more
NCT00853112 (CTgov)	Phase 2	Familial Primary Pulmonary Hypertension	48	placebo (Placebo)	xffmrlsmef(yxksutkyfo) = aeftibgpoy kxsinkhmld (nkhuvrjahu, cgpnrtncfl - arekwbvsvu) View more	-	24 Oct 2017
				PF-00489791 (PF-00489791 1 mg)	xffmrlsmef(yxksutkyfo) = cpaqzbrwgi kxsinkhmld (nkhuvrjahu, jnyzgsluut - yesasftnjt) View more
NCT01200394 (Pubmed \| J Am Soc Nephrol) Manual	Phase 2	Proteinuria \| Diabetic Nephropathies	256	PF-00489791	(vtcsfmhbtu) = ocfwukaslk irhacoupva (jtjghynpfu )	Positive	01 Nov 2016
				Placebo	(vtcsfmhbtu) = qfhjilhxjt irhacoupva (jtjghynpfu )
NCT02319148 (CTgov)	Phase 1	-	22	PF-00489791 (PF-00489791 20 mg)	jrinzuuuwj(fkualomwog) = cwysqndwdw inwtiufwrv (cmgicdwtfs, pwctdccdzg - xuoywxvjti) View more	-	16 Sep 2016
				Itraconazole+PF-00489791 (PF-00489791 20 mg + Itraconazole 200 mg)	jrinzuuuwj(fkualomwog) = aoksmydbzb inwtiufwrv (cmgicdwtfs, nztknxljpm - gwjtfravlo) View more